The genus Cuscuta (Convolvolaceac): An updated review on indigenous uses, phytochemistry, and pharmacology

Cuscuta, commonly known as dodder, is a genus of family convolvolaceace. Approximately 170 species of Cuscuta are extensively distributed in temperate and subtropical areas of the world. Species of this genus are widely used as essential constituents in functional foods and traditional medicinal systems. Various parts of many members of Cuscuta have been found efficacious against a variety of diseases. Phytochemical investigations have confirmed presence of biologically active moieties such as flavonoids, alkaloids, lignans, saponines, phenolics, tannins, and fatty acids. Pharmacological studies and traditional uses of these plants have proved that they are effective antibacterial, antioxidant, antiostioporotic, hepatoprotective, anti-inflammatory, antitumor, antipyretic, antihypertensive, analgesic, anti hair fall, and antisteriogenic agents.


Introduction
Plant-based medicines are an integral part of virtually all cultures since immemorial times. The journey of information from prehistoric texts to various indigenous folklores and modern preparations have witnessed the presence of bioactive moieties with therapeutic potential in these herbs (1)(2)(3)(4). The immense population of current allopathic products is embedded in nature. More than half of the clinically approved drugs in the world are either natural products or their modifications. Higher plants being an endless reservoir contribute above one fourth. The remarkable resurgence of interest in nature to explore pharmaceutical and nutraceutical agents is still marching towards new horizons (5)(6)(7).
Ever growing consumption of natural products by local masses has forcefully motivated the scientists to acquire systematic, elaborated, and practical knowledge about their constituents by using advanced technologies (8). Herbal products, both as purified compounds and in the form of standard extracts, offer infinite odds for novel pharmaceutical products due to the matchless accessibility to different chemical species (9). Targetbased phytochemicals have transfigured the medicinal industry because these are not only directly utilized for treatment purposes but also act as leads and standard template for synthetics drugs (10)(11). Therefore, modern scientific investigations are turning towards traditional medicines to look for new windows of opportunities giving rise to superior pharmacologically active agents against diseases (12).
Cuscuta species are rich in bioactive constituents that exhibit a wide variety of pharmacological activities. Presence of a good deal of valuable components, broad range of biological attributes and remedial value of these plants in folk medicinal systems gives stimulation toward the concept that this genus can play an important role in discovery of new and more efficient therapeutic agents. This review is an effort to edify knowledge of its phytochemical richness, pharmacological and biological significance, and folk medicinal uses, which will enhance its value as a potent pharmaceutical precursor. anthelmintic, diuretic, and tonic as well as a treatment for itching and bilious disorders (120,121). Seeds, stem, and whole plant are utilized as prescription to treat different types of ailments. Medicinal uses of several parts of Cuscuta members are given in Table 2.
C. reflexa is a treasured medicinal herb and widely used in conventional medicinal system of various Asian countries including China, India, Bangladesh, and Thailand for treating multiple disorders (122). It is called a miracle therapeutic plant in the ethnobotany, and a wide array of chemical compounds has been isolated with diverse medicinal properties (123). C. reflexa whole plant is used to treat conjunctivitis, respiratory disorders, piles, ulcers, and stomach problems (124). The paste of whole plant mixed with latex Carica papaya causes abortions (125). In rural areas of India its juice is used against jaundice. Paste of plant is effective to
C. reflexa stems are crushed with Clerodendrum viscosum leaves and fed to cattle to treat anthrax (138). The plant is used for skin infections and dandruff (139)(140). The paste of whole plant with Achyranthes aspera is used to control excessive bleeding during menstruation (141). It is also used for treatment of bone fracture and body pain (142). In folk medicine of Bangladesh, it is used to cure tumors (17). The Tripura community of Bangladesh and Satar tribes in Nepal use this plant to cure edema, body ache and for maintenance of liver function. It is used for treating constipation, spleen diseases, diarrhea, and inflammation. Paste mixed with sesame oil is applied for curing hair fall. The decoction of stem is used to cure diarrhea, cholera, and asthma, while decoction of seeds causes depression, nausea, and vomiting (29,(143)(144)(145). Whole plant powder is used to treat jaundice by tribal people of nallamalais in Andhra Pradesh (146).
C. epithymum is a mild diuretic and used to treat sciatica and scurvy. The fresh plant is applied to the skin against scrofula derma and scleroderma. It is associated with the health of liver and kidneys and used in various formulas. It is considered a mild laxative (162)(163). The whole plant is dried and used as astringent and detersive (75). Whole plant decoction of C. campestris is used as purgative and poultice (105). The sap of C. tinctoria is used to cure ringworm and warts (79). Juice of C. gigantea plant is famous as an anti-poisonous agent (140,164). The sap of C. europaea is used as a carminative, and the extract is applied to treat psoriasis (165). Seeds and vegetative parasitic plant is used as laxative, diuretic, and pain reliever and is poisonous. The juice is used for skin treatment (166)(167). C. capitata whole plant reduces irritation of bladder and improves urinary function (80). C. hyaline is used to treat chest pain (20,24). Its infusion is used as sores washer and to prevent abortion (21,73). It is antiulcer and used against culex mosquito. C. australis is used as laxative, anthelmintic, astringent, for treatment of sores, measles and as kidney and liver tonic, emollient, sedative, and sudorific (23).
Leaves of C. japonica are considered antihypertensive (93). The sap of C. kilimanjari collected from stems is directly installed to treat ear, nose, and throat diseases in central Kenya. The whole plant is used to treat stomach ache, edema, agalactia, and in veterinary medicines (23,76). C. pedicellate is used for treatment of obesity, stomachache, to cure wounds, hypertension, as purgative, and anti-inflammatory agent (26,168). The whole plant of C. planiflora is carminative and laxative, and the stem is anti-diarrheal (23,130). C. racemosa has anti-inflammatory and diuretic effects, is also used for stomach and hepatic complaints and treatment of fresh wounds (52).

Phytochemistry
Exploration of nature's garden of medication to expose more acceptable solutions with safety is a subject of interest from prehistoric era as more than half of world population still relies on medicinal plants to sustain life. The capability of these odds to appease and treat various diseases and infirmity is undoubted. The curative plants are extensively used in pharmaceuticals, food industry mostly as functional food, agricultural, and cosmetics. Various herbs, their extracts, and prescriptions are loaded with different biologically active constituents particularly alkaloids, steroids, saponins, flavonoids, and terpenoids that are responsible for their therapeutic outcomes (27,(184)(185)(186)(187)(188)(189). Phytochemical screening of ever more medicinal plants is extremely momentous in detecting and identifying innovative sources of healing as well as commercially important compounds (190).
Chemical constituents of Cuscuta species are hostdependent. For instance, a large number of alkaloids identified in these parasitic plants are the same as those found in their alkaloid containing hosts except a very few (201). These species can synthesize flavonoids, while the study of relation between flavonoids of host and parasite is under consideration. Preliminary determination indicates that flavonoid content of various Cuscuta samples growing on different hosts is quite different (202). The most thoroughly characterized species of this genus are C. reflexa and C. chinensis (67)(68)203).
Phytochemical investigations of C. chinensis have shown that flavonoids, alkaloids, poly-saccharides, steroids, lignans, and volatile oils are mostly reported in its various parts (68). The active moieties responsible for various pharmacological activities of the C. chinensis mostly include flavonoids, lignans, quinic acid, and polysaccharide. Flavonoids are the prime biologically active components in C. chinesis. Additionally, quercetin, kaempferol, and hyperoside can serve as an index to evaluate the quality of the crude drug (209).  (188,193,210). C. chinensis and C. australis are used to prepare the famous Chinese herbal prescription Tu-Si-Zi. Phytochemical analysis was done to compare the phenolic constituents of both plants. Principal compounds of C. australis were kaempferol and astragalin while hyperoside was predominant in C. chinensis (211). Several Phytoestrogens were isolated and identified from C. chinensis. Ethanolic extract of seeds afforded three new lignans named cuscutaresinols A−C (212). In another investigative study, four new glycosidic acids called cuscutic acids A-D were isolated from the alkaline hydrolysate of the ether-insoluble resin glycoside (191). Up till now bulk of the phytochemical investigations on C. chinensis targeted the seeds while other parts of the plant have had much less attention by the researchers.
An ether insoluble resin glycoside fraction was separated from seeds of C. australis and identification and characterization of resin matrix revealed the presence of three new glycosidic acids, cuscutic acids A 1 −A 3 (213). C. racemosa like other species of the genus offers flavonoids as the chief constituent along with tannins. In another experiment alkaloids, flavonoids, tannins, and saponins have been identified (52,214).
Continued Table 3. 16 Continued Table 3.  An overview of the genus Cuscuta Noureen et al.

Pharmacological attributes
Impressive medicinal background of Cuscuta species has attracted the attention of many pharmacological researchers. A good deal of biological attributes has been studied and is listed in tabular form in Table 4.

Antioxidant
Medicinally important plants are endless reservoirs of antioxidants that enhance the antioxidant capacity of the body, which lead to a reduced risk of many diseases (234)(235). Although a diverse population of synthetic analogs is commercially available due to side effects (liver impairment and carcinogenesis) blind reliance on these formulations has been over. Therefore, plants can play a key role to fulfill prerequisite for exploration of effective, biocompatible, and economic antioxidants (236).
Many investigators have employed different Continued Kaempferol Aromadenderin Quercitin 3,5,7,30,50-pentahydroxy flavanone,  (233) qualitative and quantitative approaches to detect antioxidants in various Cuscuta species. Stem collected from different hosts and extracted with various solvents (100% methanol, 80% methanol, 100% ethanol, 80% ethanol, water, and n-hexane) were analyzed for quantity of phenolics and flavonoids content. Their antioxidant capacity was measured by using a variety of assays including reducing power, DPPH scavenging activity, percent inhibition of linoleic acid peroxidation and δ-tocopherol. It was observed that there was a strong correlation between amount of total phenolics and antioxidant capacity (13).
In another study, a correlation was established between antioxidant activity and total phenolic content of aerial parts of three Iranian Cuscuta species. C. approximate, C. monogyna and C. campestris were estimated by using DPPH microplate method. The highest concentration of phenolic compounds was found in C. monogyna and C. approximata. TPC of plant methanolic extracts was determined. Methanolic extracts of C. approximata and C. monogyna contain highest amounts of total phenolic, 56.67 mg/g and 49.59 mg/g, respectively, while antioxidant potential was in the order C. monogyna ˃ C. approximate ˃ C. campestris (14).
Ethyl acetate fraction of ethanolic extract of C. chinensis seeds possesses strongest antioxidant effect with kaempferol and quercetin as its main constituents. It hunts free radicals and inhibits liquid peroxidation (198,239). The same fraction of methanolic extract was ascertained as an effective antioxidant by DPPH free radical scavenging assay (222). Moreover, aqueous extract of C. chinensis can protect murine osteoblastic MC3T3-E1 cells against tertiary butyl hydroperoxide induced injury because of its oxidation Continued    Writhing test Swiss albino mice 100 mg/kg (257) stress management potential and functioning against mitochondria-dependent pathways (240). In another experiment, flavonoids of C. chinensis were evaluated for their protective effect against oxidative stress. The survival rate of PC12 cells having H 2 O 2 -induced apoptosis was measured. The protective effect was possibly due to scavenging of reactive oxidative species and enhanced activity of antioxidant enzyme (241). Essential oils and carotenoids separated from C. mitraeformis also showed antioxidant activity (78). These results suggest that Cuscuta plants are enriched with highly important natural antioxidants that may be used in development of functional foods and drugs effective against diseases caused by oxidative stress. Isolation, identification and possible synergism among various components may be the subject of interest for further studies.

Hepatoprotective
Anti-hepatotoxic drug designing is a major thrust area seeking the attention of natural product researchers because synthetic formulations have serious side effects. C. epithymum is traditionally used as a liver tonic. C. epithymum whole plant extracted in methanol exhibited appreciably high hepatoprotective effect against CCl 4 induced hepatotoxicity in albino rats. Elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin have confirmed hepatic damage after CCl 4 administration. C. epithymum prevented the toxic effect in both anticipatory and curative models, which may be due to the presence of various bioactive moieties, including phenolics, flavonoids, and alkaloids (185).
Many investigators have studied the curative effect of C. reflexa against liver damage induced by cisplatin, paracetamol, carbon tetrachloride, ethanol, isoniazid, and rifampicin. Various biochemical measurements were observed including ALT, AST, ALP, and total bilirubin before and after the administration of C. reflexa extract. It improved liver function by significantly reducing the serum ALT, AST, and ALP levels in affected rats comparable to standard. Histopathological examination of liver section supports the results (32,242,243).
Ethanolic extract of C. australis also appeared as liver protector against acetaminophen intoxication in an animal model. Two groups of rats were intoxicated on day eight after receiving doses of C. australis seed and stem extract separately for seven days. In untreated rats, severe periportal hepatic necrosis, considerably raised serum liver damage markers, noticeably augmented lipid peroxidation and suppressed liver antioxidant enzymes activities were witnessed. Comparative evaluation of seed and stem extract proves that stem is a more potent hepatoprotective counterpart than seed (70).
Seeds of C. chinensis are commonly employed to nourish and improve hepatic disorders in China and various other Asian countries. Oxidative stress can stimulate the development of acetaminophen-induced hepatotoxicity. Liver protecting and antioxidant activities of ethanolic and aqueous extracts of C. chinensis on acetaminophen-induced hepatotoxicity in rats. Ethanolic extract showed a significant hepatoprotective effect at an oral dose of 125 and 250 mg/kg confirmed by the measurement of various parameters and observation of liver histopathology. Comparatively same doses of the aqueous extract were found ineffective rather; it resulted in further hepatic deterioration (33). C. chinensis nanoparticles were found more effective in this regard (198,239). Thus, from the above findings it can be observed that many Cuscuta species are promising hepatoprotective agents supporting the claims of traditional healers. Further investigations on chemical components are needed to pinpoint the findings.

Antidiabetic
Diabetes mellitus is becoming a growing threat for a vast population in almost all countries of the world due to a sluggish lifestyle leading to reduced physical activity and increase in obesity (244). Methanolic and chloroform extracts of C. reflexa whole plant exhibited significant hypoglycemic activity at doses of 50, 100, and 200 mg/kg body weight. Oral glucose tolerance test was used to estimate the effect in glucose-loaded Long Evans rats (50). Administration of methanolic extract C. reflexa to glucose-loaded mice led to notable reductions in blood glucose and improved metabolic alterations, thereby justifying its traditional folkloric claims (89,245).
Antidiabetic activity of C. chinensis was evaluated in dexamethasone-induced insulin-resistant human liver carcinoma (HepG2) cells (246). C. chinensis polysaccharides can reduce blood sugar level in type-2 diabetes. Efficacy was tested on alloxan-induced diabetes in a mice model. Orally administrated doses of 300 and 600 mg/kg remarkably decreased the elevated fasting blood glucose (247)(248). In a similar study, oral administration of 200 and 400 mg/kg polysaccharides significantly lessened blood glucose along with glycosylate serum protein (249). A Chinese herbal prescription, Zhujing pill, having more than 50 % C. chinensis protected retina of diabetic rats, possibly through its antioxidation and anti-inflammatory effects (250). Recently mechanism of hypoglycemic activity of C. chinesis on type 1 diabetic disease was investigated using a rat model. Daily administration of C. chinesis extract returned fasting serum insulin and fasting blood glucose to normal value by upregulating the gene expression of hepatic and pancreas genes (251). It is crucial to continue the exploration of hypoglycaemic effect of more plants as these are blessed with similar chemical profile.

Anti-inflammatory
Inflammatory reactions play a decisive role in different phases of pathogenesis of cancer. So, there may be an assumption that anti-inflammatory drugs can induce apoptosis in cancerous cells and may be equally beneficial as preventive measure and therapy (252). Aqueous and alcoholic extracts of stem of C. reflexa and its ethyl acetate fraction showed remarkable anti-inflammatory activity in in vitro and in vivo tests. Inflammation was induced by various chemicals like histamine and lipopolysaccharide. It was observed that extracts inhibited inflammatory responses that can be related to the presence of flavonoids, phenols, and polyphenols in this plant (43)(44)253). C. reflexa significantly suppressed inflammation by reducing edema volume up to 80 % in rats as compared to standard 96.36 % (254). C. campestris markedly inhibited carrageenaninduced edema in rats by oral pretreatment with 100 mg/kg extract (47). C. chinensis, by suppressing the inflammatory responses showed the potential for treatment of brain inflammation (255). Moreover, λ-carrageenan-induced paw edema treatment by using the methanolic extract of C. chinensis seed in mice, also confirmed its anti-inflammatory effect (256). C. pedicelleta and C. arvensis were found effective against inflammation (168,257). Further studies must be conducted to clarify the mechanism and to figure out the active principle behind the activity.

Antibacterial, antifungal, and antiviral
Continuous and urgent exploration is required for new antimicrobial agents with new compositions and diverse mechanisms of action to overcome antimicrobial modifications (9). Methanolic extract of C. reflexa was found significantly active against a broad spectrum of bacterial species including S. aureus, P. aeruginosa, S. dysenteriae, S. boydii, and E. coli with impressive zone of inhibition (27,(258)(259)(260).
Xanthomonas campestris (XC) is a widely spread infectious agent causing a huge loss in food crops with visible symptoms and leave shedding. Aqueous decoction and infusion extract of C. pedicellata were evaluated for antibacterial activity against diverse pathovars of XC using in vitro well diffusion method. Inhibition zone diameter was observed from 1.0 to 5.0 cm (74). The methanolic extract also showed promising high antimicrobial activity (168). C. australis is another species having notable antibacterial effect. The 50 % methanolic extract was fractionated by hexane, ethyl acetate, and butanol with various polarities. All fractions were tested against fungal, yeast and various Gram-positive and Gram-negative bacteria. All extracts except n-hexane were found effective against different species (261). Additionally, methanolic extract of C. epithymum was also significantly active against Bordetella bronchiseptica demonstrating zone of inhibition from 10-14 mm (262). C. europaea was active against Staphylococcus aureus even higher than standard drug Amoxicillin. These results lead toward the concept that this plant can be used as a safer option against this microbe (263). Recently essential oils and carotenoids separated from C. mitraeformis were found antibacterial (78).
In addition to many other species of genus Cuscuta, C. racemose offers flavonoids as chief metabolites. Slightly positive antimicrobial activity of this plant was observed against S. aureus using dilution in a liquid medium method. Minimum inhibiting concentration was 2.0 mg/ml. Phenolic compounds are documented as antimicrobial substances. So, the activity can be ascribed to the flavonoids and tannins in the plant (52).
Several secondary metabolites like flavans, flavones, and quinic acid derivatives have been found active against HIV infection. Crude aqueous extracts of C. reflexa exhibited anti-HIV activity. Virus inhibition may be attributed to the combinatory effects of nine closely related compounds (49). An antiviral protein with significantly high inhibiting property was isolated from the aqueous extract of C. reflexa (219). Methanolic extract of C. campestris showed weak anti-HIV activity (264). A number of species have been found effective against microbes. It is recommended that further studies with isolated components instead of extracts may be more useful to identify the active compounds.

Antitumor effect
Some species of the genus Cuscuta afford alkaloids with indolic nuclei that are considered potential antitumor substances. C. chinensis is a popular antitumor prescription in the Unani medicine system. Oral administration of the plant extract at a dose of 1 g/kg noticeably delayed the appearance and growth of skin papilloma and reduced the chances of carcinoma (30). Anticancer activity of C. chinensis has been evaluated by several pharmacological studies using a variety of cell lines. Results prove that it can act as an integrative approach to encounter ever-growing disease management (22,31,(265)(266)(267).
In vivo anticancer potential of C. reflexa was determined by using murine models. Alcoholic extract and its chloroform fraction were found more potent. It showed highest toxicity against human breast cancer cell lines. Similarly, chloroform part of extract of alcohol showed considerable tumor growth inhibition, which reveals that these extracts interfere in cell proliferation to inhibit cancer (15). It can induce apoptosis in Hep3B cells (253). Phenolic components isolated from C. reflexa were also assessed in HCT116 colorectal cells amongst which 1-O-p-hydroxycinnamoylglucose could show considerable anticancer activity (10).
The seed extract of C. kotschyana induced apoptosis in breast cancer cell line (MCF7) (77). As the major active phytoconstituents of C. kotschyana are flavonols, quercetin, and kaempferol (231) and quercetin has been found to reduce cell viability of quite a lot of cancer cell lines in vitro (268)(269). Therefore, these facts are consistent with results that the exposure of MCF7 cells to C. kotschyana considerably reduced viability (77).
C. campestris also has anticancer agents (270). Detection and evaluation of phytochemicals suggested that eugenol epoxide, lutein epoxide, and lupeol epoxide formed the most active fractions and exhibited the cytotoxic effects against breast cancer cells (271). In a recent effort, efficacy of a Korean herbal formula Ga Gam Nai Go Hyan containing C. japonica against benign prostatic hyperplasia was evaluated. This herbal prescription significantly decreases prostate weight by regulating inflammatory responses and apoptosis (92). There is need to develop new technologies such as nanoparticles to improve the therapeutic effect of compounds isolated from these plants. Further efforts may be used to design sustained and targeted drug release systems to improve avoiding side effects.

Immunological effects
Ethanolic extract of C. chinensis showed considerable adjuvant potentials towards cellular and humoral immune responses in mice models and can be used as vaccine adjuvants. Extract enhanced specific antibodies (IgG, IgG1, and IgG2b) to a noticeably high level by affecting Th1 and Th2 cell functions (272). Dendritic cells play a key role in regulating immune responses and are a major target to develop immune modulators. n-butanol and methanol extracts exhibited the immunosuppressive effect on dendritic cells. Kaempferol was identified as the main flavonoid of methanol fraction. Results suggest that kaempferol has potential to treat chronic inflammatory and autoimmune diseases (273). Furthermore, aqueous extract of C. chinensis also improved the immune responses (274). C. chinensis can protect against tertiary butyl hydroperoxide induced murine osteoblastic MC3T3-E1cell injury. Aqueous extract of seeds protected cells in a dose-dependent manner by modulating the oxidative stress-induced apoptosis probably owing to its antioxidant potential (240). C. australis may act as an immunopotentiator for mammals by increasing the percentage of phagocytosis (275). C. australis hyperoside can decrease T or B lymphocyte proliferation and phagocytic activity of the peritoneal M and mediate immune regulation (276).

Effect on the neuronal system
C. chinensis can act as a neuroactive agent and improves memory by inducing cell differentiation. Glycoside of the plant induced neuronal differentiation in rat pheochromocytoma PC12 cells (277). In another experiment, C. chinensis improved memory and inhibited acetylcholinesterase activity in scopolamine-induced dysmnesia mice (278). Oral administration of its aqueous extract recovered the ischemia-induced lethal damage of neurons and prevented learning disability (51). A traditional Chinese formula Wu-Zi-Yan-Zong containing C. chinensis suppresses neuroinflammatory responses and can act as an effective therapeutic agent to prevent and treat neuroinflammatory defects (279).

Anti-aging activities
C. chinensis is an important antiaging prescription of the Chinese herbal medicinal system. Various experimental efforts have been employed to test the certainty of the claim. Polysaccharides of C. chinensis can exhibit anti-aging effects by scavenging free radicals and opposing lipid peroxidation (280). Ethanolic extract of C. chinensis significantly suppressed the non-enzymatic glycosylation of D-galactose-induced rat aging model (281). Various research reports obviously show that it can regulate immune responses, prolong cell cycle, positively affect body metabolism, improve physiology of internal body organs, and stress management, which proves its anti-aging effects (282).

Antihypertensive
Ethanolic extract of C. reflexa decreased arterial blood pressure and heartbeat rate in Pentothal anesthetized rats. Experimental data indicated that it is a non-specific depressant on all the isolated tissues tested (283). In the course of experiments, ethyl acetate fraction of C. japonica exhibited distinctive angiotensin-converting enzyme (ACE) inhibition at a dose of 400 mg/ml. Four caffeoylquinic acid derivatives were isolated from the active fraction having inhibitory effects on ACE activity. Presence of these metabolites, at least in part is responsible for the antihypertensive activity extract (229).

Anti-osteoporotic activity
C. chinensis effectively boasted tissue regeneration of damaged bones by promoting the formation of osteoblasts from their precursor cells (284). It has been demonstrated in an experimental report that aqueous extract of C. chinensis significantly stimulated the differentiation and proliferation of osteoblasts in rat bone cells, but the osteoclasts activities were inhibited (285)(286). Antagonistically antiosteoporotic effect of C. chinensis was also observed. Five flavonoids were isolated from which kaempferol and hyperoside were found osteogenic in nature (22).

Renoprotective effects
Aqueous and alcoholic extract of C. reflexa exhibited substantial diuretic activity in Wister rats. Total urine volume and Na + , K + and Cl − concentration was estimated after a dose of 300 mg/kg extract. There was a marked rise in Na + and K + excretion (45). C. chinensis has been used as a kidney tonic since ancient times. Effect of seed extract on renal function parameters in the rat model having ischemia/reperfusion-induced acute renal failure was studied. Results indicate that C. chinensis extract ameliorates renal functions and regulates urine concentration (287).

Effect on the reproductive system
C. reflexa has an antifertility effect. Methanolic extract arrested the normal estrus cycle and decreased ovarian and uterus weight in adult female mice. Flavonoids are reported as antifertility agents, and C. reflexa is rich in flavonoids, so results can be attributed to the presence of such compounds (42).
C. chinensis extract, and its isolations can improve reproductive systems of both males and females. Ethanolic extract of C. chinensis induces a relaxing effect on cavernous penile tissue and may improve erectile dysfunction conditions (288). Many formulations of C. chinensis with other herbal prescriptions enhanced penile erection, improved erectile dysfunction, infantile uteruses, and motility of sperm (154,(289)(290)(291). An herbal formula, KH-204 containing C. chinensis, ameliorates erectile dysfunction by its antioxidant and lipid profile improving property (292). Effect of various flavonoids from C. chinensis on sex hormones, and prevention of induced and threatened abortion were evaluated by measuring different parameters in a mice model (293)(294)(295)(296)(297).

Anti-mutagenic activity
Mutations elicit an innate metabolic defect in regular cellular systems and lead to morbidity and mortality in mutated organisms. Therefore, exploration for novel bioactive phytocompounds to encounter promutagenic and carcinogenic effects is a subject of keen interest (298). Preliminary evaluation of methanolic extract of C. chinensis suppressed 90 % of mutagenic effect against Trp-P-1 in the Ames test, suggesting it as a potential antimutagenic agent (299).
Mutagenic and antimutagenic effects of C. reflexa were also studied by the Ames test against well-known positive mutagens including 2-aminofluorine, 4-nitroo-phenylenediamine, and sodium azide in Salmonella typhimurium (TA 98 and TA 100) bacterial strains. The extract revealed noteworthy antimutagenic activity against 4-nitro-o-phenylenediamine and sodium azide for S. typhimurium strains (122).

Cardiovascular activities
The aging process is accompanied by so many diseases like diabetes, cancer, dementia, and cardiovascular diseases. Heart diseases, leading causes of mortality are due to cardiomyocyte apoptosis which play a key role in myocardial damage and heart failure (300)(301)(302). In an experiment, effect of polysaccharide of C. chinensis was investigated on D-galactose induced apoptosis of cardiomyocytes in an aging rate model. Apoptosis parameter evaluation indicated that polysaccharide extract decreased the apoptosis of cardiomyocytes (303). C. chinensis extract can increase coronary blood flow and decrease myocardial oxygen consumption (304).

CNS depressant activities and anti-depressant activities
Central nervous system (CNS) disorders comprise 12 % of deaths worldwide and are still a hugely challenging endeavor for health care systems. Plenty of Convolvulaceae species, including Cuscuta members, are used to treat CNS related diseases traditionally and might be used as alternatives (184).
C. campestris affects the CNS action and decreases motor activity of mice sited on a rotarod. Various tests applied indicated the CNS-depressant activity of the extract, which probably seems due to an anesthetizing effect (8,47). In another experimental trial, methanolic extract of C. reflexa served as a good anxiolytic agent in mice at a dose of 400 mg/kg (305).
C. chinensis methanolic extract considerably reduced immobility times estimated by FST forced swimming test, which reveals its antidepressant activity (306). While its aqueous extract shows CNS-depressant activity in mice by reducing motor activity and the tonic/clonic phases of electrically-induced seizures in rats (157). Recently a Chinese herbal medicine, Tiansi liquid, containing C. chinensis was evaluated for its antidepressant activity, and possible mechanism of action was predicted by in silico study (307). Capsules of C. planiflora (500 mg) prepared by a pharmacist were found effective for major depression patients. In a study period of eight weeks depression was measured before and after by Beck Depression Inventory and Hamilton Depression Inventory (308).

Effect on melanin production
C. chinensis can promote melanogenesis of amelanotic melanocytes and improved the tyrosinase activities (247)(248). Furthermore, it significantly enhanced skin melanin and tyrosinase production. It also positively affected vitiligo treatment in guinea pigs (309). Moreover, there is another report on melanogenesis effect of C. chinensis seeds aqueous and ethanolic extracts both in vitro and in vivo. The aqueous extract showed inhibitory effect on tyrosinase, while the ethanolic extract displayed the opposite effect in tyrosinase activity (160). In a similar study aqueous and ethanolic extracts of C. chinensis seeds significantly influenced the melanogenesis by regulating the activity of tyrosinase (310). Consumption of the C. chinensis extract with milk reduced the melatonin synthesis and thus ameliorated the elimination of melasma (311).
C. japonica has an inhibitory effect on mushroom tyrosinase activity (312). It can also be used to improve hyperpigmentation. It was ascertained by the treatment of alpha-melanocyte-stimulating hormoneinduced melanogenesis with aqueous extract in mouse melanoma cells (69).

Anti hair fall and anthelmintic activities
Hair loss is a feared side effect of chemotherapy and creates a psychologically distressing condition among millions of men and women due to the deprivation of their major esthetic display feature. Plants as hair growth promotors have found their use in almost all traditional medicinal systems. C. reflexa extract is useful in the treatment of alopecia by promoting hair growth (40,313). Methanolic extract of C. chinensis was used as an anthelmintic drug against Dactylogyrus intermedius in goldfish (314).

Analgesic and psychopharmacological
C. campestris has analgesic properties. The whole plant grown on Nerium indicum was studied. Acetic acid induced writhing test and heat conduction method were used to study the described activity in an animal model. A dose of 400 mg/kg methanolic extract gave significant results as compared to standard Diclofenac sodium (46). In a similar experiment, protecting response against p-benzoquinone-induced writhing was studied by giving a dose of 100 mg/kg to mice, which suggested the analgesic activity of the extract (47). C. chinensis also has a pain-relieving ability which was examined by using acetic acid-induced writhing response and formalin-induced paw licking method (256).
Petroleum ether extract of C. reflexa noticeably decreased the spontaneous activity and behavior profile of Swiss albino mice. Steroids, the major constituents of the extract may be responsible for such changes (39). C. Japonica treatment improved the cognitive function of mice in a dose-dependent manner. Novel object recognition and passive avoidance test proved that it might improve learning and memory (315).

Antipyretic and antiulcer
Antipyretics agents lessened the body temperature in fever. Efficacy of C. reflexa as an antipyretic agent was confirmed in yeast induced pyrexia in rats. Aqueous and ethanolic extracts were both found active and started rectal temperature decline after three hours of dose. A dose of 400 mg/kg weight reduced the elevated temperature approximately 83.8 % (ethanolic) and 79 % (aqueous) as compared to the standard drug (96.5 %, Paracetamol) after six hours of treatment (48). C. campestris markedly lowered the body temperature of hyperthermic and normothermic mice (47).
Lyophilized raw extract of C. racemosa possesses antiulcer activity, which was ascertained by a test showing 44.22 % rate of activity, and 37.05 % rate of cure against acute and sub-chronic models of ulcers, respectively (52).

Anticonvulsant and anti-obesity
C. epithymum have effective anticonvulsant constituents and delayed the onset of seizure (316).
Methanolic extract of C. reflexa stem demonstrated preventive effects against convulsion created by chemical agents in mice. Catecholamines levels augmented considerably. After a six-week treatment, γ-aminobutyric acid (GABA) involved in seizure activity was noticeably increased in the brains of mice (317). Ethanolic extract of C. reflexa significantly reduced convulsions by delaying onset and duration of seizures in an albino mice model. A dose of 400 mg/kg showed maximum delay in pentylenetetrazole induced convulsions (238).
C. pedicellata is widely used for management of obesity. Ethanolic extract of C. pedicellata has significantly reduced the bodyweight along with serum lipid profile in high-fat diet-fed rats (26). Recently, polyphenols are reported to possess anti-obesity activity (318).

Cytotoxicity, insecticidal, antiarthritic, and wound healing activity
The ethanolic extract C. reflexa, parasitizing Nerium oleander, exhibited promising cytotoxic activity (208). Lectin-like glycoproteins isolated from C. europaea demonstrated the cytotoxic effects of LLP and LLP on C127 and B-16 cells (319). Various extracts of the plant have larvicidal potential against mosquitoes (320). C. reflexa protects against arthritis and nephrotoxicity. A dose at 600 mg/kg considerably reduced paw edema and joint swelling up to 71.22 % (321). Aqueous and ethanolic extracts of C. reflexa stem at 200 mg/kg and 400 mg/kg were able to heal wounds in a rat model (322).

Conclusion
Cuscuta genus is a rich and diverse source of many valuable chemical components. It is loaded with flavonoids, alkaloids, lignans, polysaccharides, steroids, volatile oils, and resin glycosides. Medicinal importance of its various species is part of prehistoric texts. Traditionally it is considered a miracle genus equipped with broad spectrum of remedial values. Decoctions, extracts, paste, powder, juice, and infusions of different parts of the plants are important herbal prescriptions in traditional medicinal systems.
A lot of experimentation has been employed to verify its phytotherapy as claimed by traditional healers and local inhabitants. C. reflexa, C. chinensis, C. pedicellata, C. approximate, C. monogyna, C. campestris, and C. mitraeformis have shown impressive antioxidant activity. C. chinensis, C. australis, C. reflexa, and C. epithymum are significantly hepatoprotective in nature. Some species of Cuscuta including C. reflexa, C. chinensis, C. campestris, C. japonica, and C. kotschyana have been reported potentially antitumor against various cancer cell lines. Moreover crude extracts and compounds from the various parts possessed antibacterial, antiosteoporotic, anti-inflammatory, antihypertensive, analgesic, anti hair fall, analgesic, and antiestrogenic properties.
Rich and unrivaled medicinal history demands verification with modern scientific methodologies. Only a few of the species are thoroughly investigated up till now, especially C. reflexa and C. chinensis out of nearly 170, while the rest of the members are partially or fully undiscovered in terms of phytochemistry and pharmacology. Most of the efforts are limited to in vitro and in vivo animal models or cell line level. Very few clinical studies are reported in humans. Although a good deal of secondary metabolites with multitudinous pharmacological attributes have been isolated, identified, and characterized but most of the pharmacological investigations are extract-based. Further studies must be conducted to clarify the mechanism and to figure out the active principle behind the activity to use these compounds as leads and template in development of new drugs.